The incidence of coronary heart disease (CHD) is lower in premenopausal women than in men and post-menopausal women of the same age. The higher CHD rate after menopause is currently attributed to estrogen deficiency: many epidemiological (case-control and prospective) studies have reported a reduced risk (0.5-0.63) of CHD in post-menopausal women receiving hormone replacement therapy (HRT). Moreover, estrogens have multiple effects that would be expected to be cardioprotective, including favorable changes in lipids, endothelial function, vascular reactivity and blood flow. However, the observational studies are subject to several biases that could falsely elevate the apparent benefit of estrogens: women taking estrogens tend to be wealthier, more educated and healthier than untreated women. The american HERS (Heart and Estrogen-progestin Replacement Study; 2.763 women) is a large multicenter randomized study of secondary prevention, designed to evaluate the efficacy of HRT. Results are disappointing, since no reduced risk was observed, and the risk of CHD was even higher in women receiving HRT during the first year: 1.52 (CI 95%: 1.01-2.29). In HERS study, the treatments consisted of conjugated equine estrogens and the synthetic progestin medroxyprogesterone acetate (MPA) which are rarely used in Europe. Indeed, the effects of HRT are not equivalent depending on the dose, the route of administration, the type of progestogen. It should be emphasized that MPA, contrarily to progesterone, inhibits the beneficial effect of estrogens on lipids and experimental atherosclerosis. The route of administration of estrogens is also involved: estrogens alter hemostasis factors, and when orally administered, they have a first pass liver effect, which favors hypercoagulability. It is therefore urgent that Europeans undertake a European "HERS study" in order to investigate the possible beneficial effect of non oral estrogens (gel or patch) associated with natural progesterone.
Kuttenn, F., & Gerson, M. (2001). Hormone replacement therapy of menopause, heart and blood vessels. Archives des maladies du coeur et des vaisseaux, 94(7), 685-689.
Kuttenn F, Gerson M. Hormone replacement therapy of menopause, heart and blood vessels. Arch Mal Coeur Vaiss. 2001;94(7):685-689.
Kuttenn, F., and Michel Gerson. "Hormone replacement therapy of menopause, heart and blood vessels." Archives des maladies du coeur et des vaisseaux, vol. 94, no. 7, 2001, pp. 685-689.
The incidence of cardiovascular disease in women is negligible before natural or surgically-induced menopause, and increases after menopause. Epidemiological data suggest that estrogen replacement therapy reduces the occurrence of coronary artery, and possibly cerebrovascular, disease by 25 to 50% in treated women compared with non-users. These findings are supported by the evidence that estrogens have a beneficial effect on cholesterol metabolism and deposition, contributing to the inhibition of atherosclerotic plaque formation in arterial walls. Early reports suggested that up to 60% of the protective effect of estrogens on coronary artery disease was attributable to favourable changes in plasma lipids. Reanalysis of the data indicated that the lipid changes probably account for approximately 25% of the cardioprotective effect of estrogens and that other effects are, therefore, likely to be important. The influence of estrogens on carbohydrate metabolism, atheroma formation and cardiovascular haemodynamics may also play an integral role in the overall beneficial effect of the hormones. Animal and human studies have shown that the administration of estrogens leads to a restoration of endothelial function, an increase in cardiac output, an increase in arterial flow velocity, a decrease in vascular resistance, and a decrease in systolic and diastolic blood pressure. Recent studies on hormone replacement regimens have shown that estrogens may favourably affect fibrinolysis and reduce plasma fibrinogen to premenopausal levels. Despite these effects of estrogens the recent Heart and Estrogen/Progestin Replacement Study (HERS) failed to show a cardioprotective effect of hormone replacement therapy (HRT) in elderly women with coronary artery disease. However, the HERS study has several limitations and stands alone against the large body of evidence that suggest that HRT may reduce cardiovascular mortality and morbidity.
After menopause, both systolic (SBP) and diastolic (DBP) blood pressure (BP) become higher in women than in men of the same age, suggesting that estrogen deficiency may influence the age-related increase in BP. We studied 30 postmenopausal women (mean age, 55 +/- 5.7 years; time from menopause, 2-5 years) affected by mild hypertension with no target-organ complications by means of 24-h BP monitoring. None of the group were undergoing estrogen replacement therapy or taking antihypertensive drugs. According to a randomized, double-blind protocol, subjects received patches of transdermal estradiol-17beta (E2) or a matched placebo, with crossover after a 7-day washout period. In 12 patients the 24-h peak-to-trough variation in SBP and DBP amounted to less than 10% (nondippers). Administration of E2 significantly decreased 24-h SBP and DBP in the whole cohort (P < .05). Furthermore, E2 restored the expected reduction in BP during nighttime in the nondipper subgroup. It is well known that estrogen replacement therapy protects against the development of both cardiovascular diseases and stroke. Our data suggest that this activity could be attributed, at least in part, to the activity of E2 in preserving physiologic circadian fluctuation of BP.
Migraine is a neurologic disorder that disproportionately affects women and undergoes important changes across the menopausal transition. Estrogen fluctuations contribute to migraine expression and underlie the 3:1 female-to-male prevalence. Perimenopause, marked by hormonal variability and rising cardiometabolic risk, presents unique diagnostic and therapeutic challenges. Despite its high prevalence, evidence specific to perimenopausal and postmenopausal women remains limited. This review synthesizes current evidence on the epidemiology, pathophysiology, and management of migraine across the menopausal transition, with attention to hormone therapy, comorbidities, and emerging treatments. We conducted a narrative review of clinical and translational studies published within the past 5 years, supplemented by seminal mechanistic, epidemiologic, and guideline-defining studies published earlier. Relevant guideline statements from neurology, gynecology, and cardiovascular societies were also incorporated. Unstable estradiol and progesterone levels during perimenopause can worsen migraine frequency and predictability. Migraine without aura often improves after menopause, whereas migraine with aura tends to persist and independently increases the risk of ischemic stroke and other vascular events. Midlife comorbidities-including vasomotor symptoms, sleep disturbance, mood disorders, and metabolic disease-further complicate management. Menopausal hormone therapy has variable effects. Oral estrogen, particularly at higher doses, may worsen migraine and elevate vascular risk, especially in women with aura. In contrast, low-dose transdermal estrogen-recommended by the North American Menopause Society-appears safer and better tolerated. Continuous progestogen regimens may reduce withdrawal-related attacks compared with cyclic regimens. Nonhormonal options, particularly selective norepinephrine reuptake inhibitors, may be considered when vasomotor symptoms coexist, whereas migraine-specific prevention should follow established evidence-based therapies. Traditional migraine therapies (triptans, NSAIDs, beta-blockers, topiramate, antidepressants) remain central but require tailoring to vascular, bone, and metabolic health. Newer agents-including calcitonin gene-related peptide monoclonal antibodies, gepants, and ditans-offer effective, non-vasoconstrictive alternatives, especially for women with cardiovascular contraindications. Migraine during the menopausal transition reflects the interplay between hormonal dynamics and systemic health. Management requires balancing efficacy with vascular and metabolic safety while incorporating patient preferences. Evidence gaps include the lack of trials stratified by menopausal stage or migraine subtype. Multidisciplinary, menopause-informed care and prospective studies are needed to optimize outcomes in this population.
The study aims to assess the use of menopausal hormone therapy beyond age 65 years and its health implications by types of estrogen/progestogen, routes of administration, and dose strengths. Using prescription drug and encounter records of 10 million senior Medicare women from 2007-2020 and Cox regression analyses adjusted for time-varying characteristics of the women, we examined the effects of different preparations of menopausal hormone therapy on all-cause mortality, five cancers, six cardiovascular diseases, and dementia. Compared with never use or discontinuation of menopausal hormone therapy after age 65 years, the use of estrogen monotherapy beyond age 65 years was associated with significant risk reductions in mortality (19% or adjusted hazards ratio, 0.81; 95% CI, 0.79-0.82), breast cancer (16%), lung cancer (13%), colorectal cancer (12%), congestive heart failure (CHF) (5%), venous thromboembolism (3%), atrial fibrillation (4%), acute myocardial infarction (11%), and dementia (2%). For the use of estrogen and progestogen combo-therapy, both E+ progestin and E+ progesterone were associated with increased risk of breast cancer by 10%-19%, but such risk can be mitigated using low dose of transdermal or vaginal E+ progestin. Moreover, E+ progestin exhibited significant risk reductions in endometrial cancer (45% or adjusted hazards ratio, 0.55; 95% CI, 0.50-0.60), ovarian cancer (21%), ischemic heart disease (5%), CHF (5%), and venous thromboembolism (5%), whereas E+ progesterone exhibited risk reduction only in CHF (4%). Among senior Medicare women, the implications of menopausal hormone therapy use beyond age 65 years vary by types, routes, and strengths. In general, risk reductions appear to be greater with low rather than medium or high doses, vaginal or transdermal rather than oral preparations, and with E2 rather than conjugated estrogen.